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Direct Comparison of (N)-Methanocarba and Ribose-Containing 2‑Arylalkynyladenosine Derivatives as A3 Receptor Agonists
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posted on 2020-02-13, 22:44 authored by Dilip
K. Tosh, Veronica Salmaso, Harsha Rao, Ryan Campbell, Amelia Bitant, Zhan-Guo Gao, John A. Auchampach, Kenneth A. JacobsonA side-by-side
pharmacological comparison of ribose and (N)-methanocarba
(bicyclo[3.1.0]hexane) nucleosides as A3AR agonists indicated
that the bicyclic pseudoribose ring constraint provided higher affinity/selectivity
at human and mouse A3AR. The mean affinity enhancement
for 5 pairs of 5′-methylamides was 11-fold at hA3AR and 42-fold at mA3AR. Novel C2-(5-fluorothien-2-ylethynyl)
substitution enhanced affinity in the methanocarba but not ribose
series, with highly hA3AR-selective 16 (MRS7334)
displaying Ki 280 pM and favorable pharmacokinetics and
off-target activity profile. Molecular dynamics comparison of 16 and its corresponding riboside 8 suggested
a qualitative entropic advantage of 16 in hA3AR binding. The 5-F substitution tended to increase hA3AR affinity (cf. 5-Cl) for methanocarba but not ribose derivatives.
A representative methanocarba agonist 4 was shown to
interact potently exclusively with A3AR, among 240 GPCRs
and 466 kinases. Thus, despite added synthetic difficulty, the (N)-methanocarba
modification has distinct advantages for A3AR agonists,
which have translational potential for chronic disease treatment.